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Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others in order to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2006, childhood cancer mortality has decreased by more than 50%. Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Wilms tumor is a curable disease in the majority of affected children. Approximately 500 cases are diagnosed in the United States each year. Since the 1980s, the 5-year survival rate for Wilms tumor has been consistently above 90%. This favorable outcome occurred despite reductions in the length of therapy, dose of radiation, extent of fields irradiated, and the percentage of patients receiving radiation therapy. The prognosis for patients with Wilms tumor is related not only to the stage of disease at diagnosis, the histopathologic features of the tumor, patient age, and tumor size, but also to the team approach provided to each patient by the pediatric surgeon, radiation oncologist, and pediatric oncologist (COG-AREN9404).[4,5,6,7] Patients who develop Wilms tumor in their second decade of life have a poorer survival (5-year survival, 63%) than younger patients with Wilms tumor.
In an analysis of Wilms tumor patients in the Surveillance, Epidemiology and End Results database, adults (n = 152) had a statistically worse overall survival (OS) (69% vs. 88%, P < .001) than pediatric patients (n = 2,190), despite previous studies showing comparable outcome when treated on protocol.[9,10] Adults with Wilms tumor were more likely than pediatric patients to be staged as having localized disease, to not receive any lymph node sampling, and to not receive any radiation treatment. The investigators recommended that all adult patients diagnosed with Wilms tumor should undergo lymph node sampling and that there should be close collaboration with pediatric surgeons and oncologists in treatment planning. The Children's Oncology Group has increased the enrollment age for their Wilms tumor trials to include patients up to age 30 years.
Congenital Anomalies and Syndromes Predisposing to Wilms Tumor
Wilms tumor typically develops in otherwise healthy children; however, approximately 10% of children with Wilms tumor have a congenital anomaly. Children with Wilms tumor may have associated urinary tract anomalies, including hemihypertrophy, cryptorchidism, and hypospadias. Children may have a recognizable phenotypic syndrome (including overgrowth disease, aniridia, genetic malformations, and others). These syndromes have provided clues to the genetic basis of the disease. The phenotypic syndromes have been divided into overgrowth and nonovergrowth categories.
Screening Children Predisposed to Wilms Tumor
Children with a significantly increased predisposition to develop Wilms tumor (e.g., most children with Beckwith-Wiedemann syndrome, WAGR syndrome, Denys-Drash syndrome, idiopathic hemihypertrophy, or sporadic aniridia) should be screened with ultrasound every 3 months at least until they reach age 8 years.[13,14,15,30]
Approximately 10% of patients with Beckwith-Wiedemann syndrome will develop a malignancy, with either Wilms tumor or hepatoblastoma being the most common, although adrenal tumors can also occur. Children with hemihypertrophy are also at risk for developing liver and adrenal tumors. Screening with abdominal ultrasound and serum alpha-fetoprotein is suggested until age 4 years; after age 4, most hepatoblastomas will have occurred, and imaging may be limited to renal ultrasound, which is quicker and does not require the child to fast for the exam.
Children with Klippel-Trénaunay syndrome, a unilateral limb overgrowth syndrome, had been considered to be at increased risk for developing Wilms tumor. The risk of Wilms tumor in children with Klippel-Trénaunay syndrome, when assessed using the National Wilms Tumor Study (NWTS) database, was no different than in the general population and routine ultrasound surveillance is not recommended.
Genetics of Wilms Tumor
Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of at least ten genes. Several, but not all, will be discussed here.
Wilms tumor 1gene (WT1)
The WT1 gene is located on the short arm of chromosome 11 (11p13). The normal function of WT1 is required for normal genitourinary development and is important for differentiation of the renal blastema. Germline mutations in WT1 have been found in about 2% of phenotypically normal children with Wilms tumor. Germline WT1 mutations in children with Wilms tumor does not confer a poor prognosis per se. The offspring of those with germline mutation in WT1 may also be at increased risk of developing Wilms tumor. Because deletion of WT1 was the first mutation found to be associated with Wilms tumor, WT1 was assumed to be a conventional tumor suppressor gene. However, non-inactivating mutations can result in altered WT1 protein function that also results in Wilms tumor, such as in the Denys-Drash syndrome.
WT1 mutation is more common in those children with Wilms tumor and one of the following:
WT1mutation, aniridia, and genitourinary malformation
The observation that lead to the discovery of WT1 was that children with WAGR syndrome (aniridia, genitourinary anomalies, and mental retardation) were at high risk (>30%) for developing Wilms tumor. Germline mutations were then identified at chromosome 11p13 in children with WAGR syndrome. Deletions involved a set of contiguous genes that included WT1 and the PAX6 gene (responsible for aniridia). Aniridia is characterized by hypoplasia of the iris and it occurs in sporadic or familial cases and has an autosomal dominant inheritance. Mutations in the PAX6 gene lead to aniridia. The PAX6 gene is located on chromosome 13 closely associated with the WT1 gene, deletion of which confers the increased risk of Wilms tumor. Some of the sporadic cases of aniridia are caused by large chromosomal deletions that also include the Wilms tumor gene – WT1. This results in an increased relative risk of 67-fold (95% confidence interval [CI], 8.1–241) of developing Wilms tumor in children with sporadic aniridia. Patients with sporadic aniridia and a normal WT1 gene, however, are not at increased risk for developing Wilms tumor. Children with familial aniridia generally have a normal WT1 gene and are not at an increased risk of Wilms tumor. The mental retardation in WAGR syndrome may be secondary to deletion of other genes including SLC1A2 or BDNF (brain-derived neurotrophic factor).
The incidence of Wilms tumor in children with sporadic aniridia is estimated to be about 5%. Patients with sporadic aniridia should be screened with ultrasound every 3 months until they reach age 8 years, unless genetic testing confirms that they are negative for WT1.[15,30]
Monitoring for late renal failure
Children with WAGR syndrome or other germline WT1 mutations are at increased risk of eventually developing hypertension, nephropathy, and renal failure and should be monitored throughout their lives. Patients with Wilms tumor and aniridia without genitourinary abnormalities are at lesser risk but should be monitored for nephropathy or renal failure. Children with Wilms tumor and any genitourinary anomalies are also at increased risk for late renal failure and should be monitored. Features associated with germline WT1 mutations that increase the risk for developing renal failure are stromal predominant histology, bilaterality, intralobular nephrogenic rests, and Wilms tumor diagnosed before age 2 years.
Activating mutations of the beta-catenin gene (CTNNB1) have been reported to occur in 15% of Wilms tumor patients. In one study, all but one tumor with a beta-catenin mutation had a WT1 mutation and at least 50% of the tumors with WT1 mutations had a beta-catenin mutation.[39,40] That CTNNB1 mutations are rarely found in the absence of a WT1 or WTX mutation suggests that activation of beta-catenin in the presence of intact WT1 protein must be inadequate to promote tumor development.[41,42]
WT1 mutations and 11p15 loss of heterozygosity are associated with relapse in patients with very low-risk Wilms tumor who do not receive chemotherapy. These may provide biomarkers to stratify patients in the future.
Wilms tumor 2gene (WT2)
A second Wilms tumor locus, WT2 gene, maps to an imprinted region of chromosome 11p15.5, which, when constitutional, causes the Beckwith-Wiedemann syndrome. About 3% of children with Wilms tumors have constitutional epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. These children may be more likely to have bilateral Wilms tumor or familial Wilms tumor. There are several candidate genes at the WT2 locus, comprising the two independent imprinted domains IGF2/H19 and KIP2/LIT1. Loss of heterozygosity, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally inactive ones. A loss or switch of the imprint for genes (change in methylation status) in this region has also been frequently observed and results in the same functional aberrations. A study of 35 sporadic primary Wilms tumors suggests that more than 80% have somatic loss of heterozygosity or loss of imprinting at 11p15.5. The mechanism resulting in loss of imprinting can be either genetic mutation or epigenetic change of methylation.[36,44] Loss of imprinting or gene methylation are rarely found at other loci, supporting the specificity of loss of imprinting at IGF2. Interestingly, Wilms tumors in Asian children are not associated with either nephrogenic rests or IGF2 loss of imprinting.
Beckwith-Wiedemann syndrome results from constitutional loss of imprinting or heterozygosity of WT2. Observations suggest genetic heterogeneity in the etiology of Beckwith-Wiedemann syndrome with differing levels of association with risk of tumor formation. Molecularly defined subsets of Beckwith-Wiedemann patients may not require ultrasound screening for malignancies. Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, though metachronous bilateral disease is also observed.[15,16,17] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the NWTS.[17,49,50]
Wilms tumor gene on the X chromosome(WTX)
A third gene, WTX, has been identified on the X chromosome and plays a role in normal kidney development. WTX mutations were identified in 17% of Wilms tumors, equally distributed between males and females. This gene is inactivated in approximately one-third of Wilms tumors but germline mutations have not been observed in patients with Wilms tumor.
Additional genes have been implicated in the pathogenesis and biology of Wilms tumor:
Genetics of Familial Wilms Tumor
Despite the number of genes that appear to be involved in the development of Wilms tumor, hereditary Wilms tumor is uncommon, with approximately 2% of patients having a positive family history for Wilms tumor. Siblings of children with Wilms tumor have a low likelihood of developing Wilms tumor. The risk of Wilms tumor among offspring of persons who have had unilateral (sporadic) tumors is less than 2%. Two familial Wilms tumor genes have been localized to FWT1 (17q12-q21) and FWT2 (19q13.4).[62,63,64]
Bilateral Wilms Tumor
About 4% to 5% of patients have bilateral Wilms tumors, but these are not usually hereditary. Many bilateral tumors are present at the time Wilms tumor is first diagnosed (i.e., synchronous), but a second Wilms tumor may also develop later in the remaining kidney of 1% to 3% of children treated successfully for Wilms tumor. The incidence of such metachronous bilateral Wilms tumors is much higher in children whose original Wilms tumor was diagnosed before age 12 months and/or whose resected kidney contains nephrogenic rests. Periodic abdominal ultrasound is recommended for early detection of metachronous bilateral Wilms tumor as follows:[63,64]
Clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, neuroepithelial tumor of the kidney, and cystic partially-differentiated nephroblastoma are childhood renal tumors unrelated to Wilms tumor.[66,67] (Refer to the Cellular Classification section of this summary for more information.)
Although most patients with a histologic diagnosis of Wilms tumor fare well with current treatment, approximately 10% of patients have histopathologic features that are associated with a poorer prognosis, and in some types, with a high incidence of relapse and death. Wilms tumor can be separated into three prognostic groups on the basis of histopathology—favorable histology, anaplastic histology, and nephrogenic rests.
Histologically, Wilms tumor mimics development of a normal kidney consisting of three cell types: blastemal, epithelial (tubules), and stromal. Not all tumors are triphasic, and monophasic patterns may present diagnostic difficulties. While associations between histologic features and prognosis or responsiveness to therapy have been suggested, with the exception of anaplasia, none of these features have reached statistical significance and therefore do not direct the initial therapy.
Anaplastic histology accounts for about 10% of Wilms tumors. Anaplastic histology is the single most important histologic predictor of response and survival in patients with Wilms tumor. Tumors occurring in older patients (aged 10–16 years) have a higher incidence of anaplastic histology. There are two histologic criteria for anaplasia, both of which must be present for the diagnosis. They are the presence of multipolar polyploid mitotic figures with marked nuclear enlargement and hyperchromasia. Changes on 17p consistent with mutations in the p53 gene have been associated with foci of anaplastic histology. All of these characteristics lend support to the hypothesis that anaplasia evolves as a late event from a subpopulation of Wilms tumor cells that have acquired additional genetic lesions. Anaplasia correlates best with responsiveness to therapy rather than to aggressiveness. It is most consistently associated with poor prognosis when it is diffusely distributed and when identified at advanced stages. These tumors are more resistant to the chemotherapy traditionally used in children with favorable-histology Wilms tumor. This is the reason why focal anaplasia and diffuse anaplasia are differentiated, both pathologically and therapeutically. Focal anaplasia is defined as the presence of one or a few sharply localized regions of anaplasia within a primary tumor. Focal anaplasia does not confer as poor a prognosis as does diffuse anaplasia.[5,6,7]
Nephrogenic rests are abnormally retained embryonic kidney precursor cells arranged in clusters. Nephrogenic rests are found in about 1% of unselected pediatric autopsies, 35% of kidneys with unilateral Wilms tumors, and in nearly 100% of kidneys with bilateral Wilms tumors.[8,9] The term nephroblastomatosis is defined as the presence of diffuse or multifocal nephrogenic rests. There are two types: intralobar nephrogenic rests and perilobar nephrogenic rests. Diffuse hyperplastic perilobar nephroblastomatosis is defined as nephroblastomatosis forming a thick rind around one or both kidneys and is considered a preneoplastic condition. Patients with any type of nephrogenic rest in a kidney removed for nephroblastoma should be considered at increased risk for tumor formation in the remaining kidney. This risk decreases with patient age. Extrarenal nephrogenic rests rarely occur, but may develop into extrarenal Wilms tumor.
Clear Cell Sarcoma of the Kidney
Clear cell sarcoma of the kidney is not a Wilms tumor variant, but it is an important primary renal tumor associated with a significantly higher rate of relapse and death than favorable-histology Wilms tumor. In addition to pulmonary metastases, clear cell sarcoma also spreads to bone, brain, and soft tissue. The classic pattern of clear cell sarcoma of the kidney is defined by nests or cords of cells separated by regularly spaced fibrovascular septa. Previously, relapses have occurred in long intervals after the completion of chemotherapy (up to 10 years), however with current therapy relapses after 3 years are uncommon. The brain is a frequent site of recurrent disease.[14,15]
While little is known about the biology of clear cell sarcoma of the kidney, the t(10;17)(q22;p13) translocation has been reported in clear cell sarcoma of the kidney. As a result of the translocation, the YWHAE-FAM22 fusion transcript is formed; this transcript was detected in 12% of clear cell sarcoma of the kidney cases in one series.
Rhabdoid Tumors of the Kidney
Rhabdoid tumors are extremely aggressive malignancies that generally occur in infants and young children. The most common locations are the kidney and central nervous system (CNS) (atypical teratoid/rhabdoid tumor), although rhabdoid tumors can also arise in most soft tissue sites. Initially they were thought to be a rhabdomyosarcomatoid variant of Wilms tumor when they occurred in the kidney.
Histologically, the most distinctive features of rhabdoid tumors of the kidney are rather large cells with large vesicular nuclei, a prominent single nucleolus, and in some cells, the presence of globular eosinophilic cytoplasmic inclusions. A distinct clinical presentation with fever, hematuria, young age (mean age 11 months), and high tumor stage at presentation suggests a diagnosis of rhabdoid tumor of the kidney. Approximately two-thirds of patients will present with advanced stage. Bilateral cases have been reported. Rhabdoid tumors of the kidney tend to metastasize to the lungs and the brain. As many as 10% to 15% of patients with rhabdoid tumors of the kidney also have CNS lesions. Relapses occur early (median time from diagnosis is 8 months).[18,20]
Rhabdoid tumors in all anatomical locations have a common genetic abnormality—the mutation and/or deletion of the SMARCB1 (also called hSNF5 or INI1) gene located at chromosome 22q11. This gene encodes a component of the SWI/SNF chromatin remodeling complex that has an important role in transcriptional regulation.[21,22] Based on gene expression analysis in rhabdoid tumors, it is hypothesized that rhabdoid tumors arise within early progenitor cells during a critical developmental window in which loss of SMARCB1 directly results in repression of neural development, loss of cyclin-dependent kinase inhibition, and trithorax/polycomb dysregulation. Identical mutations may give rise to a brain or kidney tumor. Germline mutations of SMARCB1 have been documented for patients with one or more primary tumors of the brain and/or kidney, consistent with a genetic predisposition to the development of rhabdoid tumors.[24,25] Approximately 35% of patients with rhabdoid tumors have germline SMARCB1 alterations. In most cases, the mutations are de novo, and not inherited from a parent. Germline mosaicism has been suggested for several families with multiple affected siblings. It appears that those patients with germline mutations may have the worst prognosis.
Rhabdoid predisposition syndrome
Early-onset, multifocal disease and familial cases strongly support the possibility of a rhabdoid predisposition syndrome. This has been confirmed by the presence of constitutional mutations of SMARCB1 in rare familial cases and in a subset of patients with apparently sporadic rhabdoid tumors. In a cohort of 74 rhabdoid tumors, 60% of the tumors occurring before age 6 months were linked to the presence of a germline mutation. However, in this same series, tumors that occurred after age 2 years were also found to be associated with germline mutations (7 of 35 cases). Germline analysis is suggested for all individuals with rhabdoid tumors, whatever their ages. Genetic counseling is recommended given the low-but-actual risk of familial recurrence. In cases of mutations, parental screening should be considered, although such screening carries a low probability of positivity. Prenatal diagnosis is feasible and should be considered.
Recommendations for surveillance in patients with germline SMARCB1 mutations have been developed based on the epidemiology and clinical course of rhabdoid tumors. These recommendations were developed by a group of pediatric cancer genetic experts (including oncologists, radiologists, and geneticists). They have not been formally studied to confirm the benefit of screening patients with germline SMARCB1 mutations. The aggressive natural history of the disease, apparently high penetrance, and well-defined age of onset for CNS atypical teratoid/rhabdoid tumor suggest that screening could prove beneficial. Given the potential survival benefit of surgically resectable disease, it is postulated that early detection might improve overall survival. From birth to age 1 year, it is suggested that patients have thorough physical and neurologic examinations, as well as head ultrasounds monthly to assess for the development of a CNS tumor. It is suggested that patients undergo abdominal ultrasounds with focus on the kidneys every 2 to 3 months to assess for renal lesions. From age 1 year to approximately age 4 years, after which the risk of developing a new rhabdoid tumor rapidly declines, it is suggested that brain and spine magnetic resonance imaging (MRI) and abdominal ultrasound be performed every 6 months.
Congenital Mesoblastic Nephroma
Mesoblastic nephroma comprises about 5% of childhood kidney tumors. It is the most common kidney tumor found in infants younger than 3 months. The median age of diagnosis is 1 to 2 months and more than 90% of cases appear within the first year of life. Twice as many males are diagnosed as females. The diagnosis should be questioned when applied to individuals older than 2 years. When diagnosed in the first 7 months of life, the 5-year event-free survival (EFS) rate is 94% and the overall survival (OS) rate is 96%.
Grossly, mesoblastic nephromas appear as solitary, unilateral masses indistinguishable from nephroblastoma. Microscopically, they consist of spindled mesenchymal cells. They can be divided into two major types: classic and cellular. Classic mesoblastic nephroma is often diagnosed by prenatal ultrasound or within 3 months after birth and closely resembles infantile fibromatosis. Infantile fibrosarcoma and cellular mesoblastic nephroma contain the same t(12;15)(p13;q25) chromosomal translocation suggestive of a potential linkage. The risk for recurrence within mesoblastic nephroma is closely associated with the presence of a cellular component and with stage.
Renal Cell Carcinoma
Malignant epithelial tumors arising in the kidneys of children account for more than 5% of new pediatric renal tumors; therefore, they are more common than clear cell sarcoma of the kidney or rhabdoid tumors of the kidney. Renal cell carcinoma (RCC), the most common primary malignancy of the kidney in adults, occurs rarely in children younger than 15 years. In the older age group of adolescents (aged 15–19 years), approximately two-thirds of renal malignancies are RCC. The annual incidence rate is approximately 4 per 1 million children compared with an incidence of Wilms tumor of the kidney that is at least 29-fold higher. RCC in young patients has a different genetic and morphologic spectrum than that seen in older adults.[35,36,37,38]
RCC may be associated with other conditions, including the following:
Screening for the VHL gene is available. To detect clear cell renal carcinoma in these individuals when the lesions are less than 3 cm and nephron-sparing surgery can be performed, annual screening with abdominal ultrasound or MRI is recommended beginning at age 8 to 11 years.
Succinate dehydrogenase (SDHB, SDHC, and SDHD) is a Krebs cycle enzyme gene that has been associated with the development of familial renal cell carcinoma occurring with pheochromocytoma/paraganglioma. Germline mutations in a subunit of the gene have been reported in individuals with renal cancer with no history of pheochromocytoma.[43,44]
Indications for germline genetic testing of children and adolescents with RCC to screen for a related syndrome are described in Table 1.
Pediatric RCC differs histologically from the adult counterparts. Although the two main morphological subgroups of papillary and clear cell can be identified, about 25% of RCCs show heterogeneous features that do not fit into either one of these categories. Childhood RCCs are more frequently of the papillary subtype (20%–50% of pediatric RCCs) and can sometimes occur in the setting of Wilms tumor, metanephric adenoma, and metanephric adenofibroma.
Translocation-positive carcinomas of the kidney are recognized as a distinct form of RCC and may be the most common form of RCC in children. They are characterized by translocations involving the transcription factor E3 (TFE3) located on Xp11.2. The TFE3 gene may partner with one of the following genes:
Another less common translocation subtype, t(6;11)(p21;q12), involving a fusion Alpha/TFEB, induces overexpression of transcription factor EB (TFEB). The translocations involving TFE3 and TFEB induce overexpression of these proteins, which can be identified by immunohistochemistry. Prior exposure to chemotherapy is the only known risk factor for the development of Xp11 translocation RCCs. The postchemotherapy interval ranged from 4 to 13 years. All reported patients received either a DNA topoisomerase II inhibitor and/or an alkylating agent.[38,58] Controversy exists as to the biological behavior of the translocation RCC in children and young adults. Whereas some series have suggested a good prognosis when RCC is treated with surgery alone despite presenting at a higher stage (III/IV) than TFE-RCC, a meta-analysis reports that these patients have poorer outcomes.[59,60,61] Recurrences have been reported 20 to 30 years after the initial resection of the translocation-associated RCC. VEGFR-targeted therapies and mTOR inhibitors seem to be active in Xp11 translocation metastatic RCC.
RCC may present with an abdominal mass, abdominal pain, or hematuria. In a series of 41 children with RCC, the median age was 124 months with 46% presenting with localized stage I and stage II disease, 29% with stage III disease, and 22% with stage IV disease using the Robson classification system. The sites of metastases were the lungs, liver, and lymph nodes. EFS and OS were each about 55% at 20 years posttreatment. Patients with stage I and stage II disease had an 89% OS rate, while those with stage III and stage IV disease had a 23% OS rate at 20 years posttreatment. An important difference between the outcomes in children and adults with RCC is the prognostic significance of local lymph node involvement. Adults presenting with RCC and involved lymph nodes have a 5-year OS of approximately 20%, but the literature suggests that 72% of children with RCC and local lymph node involvement at diagnosis (without distant metastases) survive their disease. In another series of 49 patients from a population-based cancer registry, the findings were essentially confirmed. In this series, 33% of the patients had papillary subtype, 22% had translocation type, 16% were unclassified, and 6% had clear-cell subtype. Survival at 5 years was 96% for patients with localized disease, 75% for patients with positive regional lymph nodes, and 33% for patients with distant metastatic RCC.
Some nephrogenic rests may become hyperplastic which may produce a thick rind of blastemal or tubular cells that enlarge the kidney. The diagnosis may be made radiographically, most readily by magnetic resonance imaging, in which the homogeneity of the hypointense rind-like lesion on contrast-enhanced imaging differentiates it from Wilms tumor. Biopsy often cannot discriminate Wilms tumor from these hyperplastic nephrogenic rests. Differentiation may occur following the administration of chemotherapy. Current recommendations are for treatment with vincristine and dactinomycin until nearly complete resolution as determined by imaging. Even with treatment (vincristine and dactinomycin), about half of children diagnosed with nephroblastomatosis will develop Wilms tumor within 36 months. In a series of 52 patients, three patients died of recurrent Wilms tumor. In treated children, as many as one-third of Wilms tumors are anaplastic, probably as a result of selection of chemotherapy-resistant tumors, so early detection is critical. Patients are followed by imaging at a maximum interval of 3 months for a minimum of 7 years. Given the high incidence of bilaterality and the subsequent Wilms tumors, renal-sparing surgery is indicated. These patients will be eligible for treatment on the COG-AREN0534 trial with vincristine and dactinomycin.
Neuroepithelial Tumors of the Kidney
Neuroepithelial tumors of the kidney (NETK) are extremely rare and demonstrate a unique proclivity for young adults. It is a highly aggressive neoplasm, more often presenting with penetration of the renal capsule, extension into the renal vein, and metastases.[67,68] Primary NETK consist of primitive neuroectodermal tumors characterized by CD99 (MIC-2) positivity and the detection of EWS/FLI-1 fusion transcripts. Within NETK, focal, atypical histologic features have been seen including clear cell sarcoma, RT, malignant peripheral nerve sheath tumors, and paraganglioma.[67,69] (Refer to the PDQ summary on Ewing Sarcoma Treatment for more information about neuroepithelial tumors.)
Desmoplastic Small Round Cell Tumor of the Kidney
Desmoplastic small round cell tumor of the kidney is a rare, small, round blue tumor of the kidney. It is diagnosed by its characteristic EWS-WT1 translocation. (Refer to the PDQ summary on Childhood Soft Tissue Sarcoma Treatment for more information about desmoplastic small round cell tumor of the kidney.)
Cystic Partially Differentiated Nephroblastoma
Cystic partially differentiated nephroblastoma is a rare cystic variant of Wilms tumor (1%) with unique pathologic and clinical characteristics. It is composed entirely of cysts and their thin septa are the only solid portion of the tumor. The septa contain blastemal cells in any amount with or without embryonal stromal or epithelial cell type. Several pathologic features distinguish this neoplasm from standard Wilms tumor. Patients with stage I disease have a 100% survival rate with surgery alone. Patients with stage II disease have an excellent outcome with tumor resection followed by postoperative vincristine and dactinomycin.
Multilocular Cystic Nephroma
Multilocular cystic nephromas are benign lesions consisting of cysts lined by renal epithelium. These lesions can occur bilaterally and a familial pattern has been reported. Multilocular cystic nephroma has been associated with pleuropulmonary blastomas, so radiographic imaging studies of the chest should be followed in patients with multilocular cystic nephroma. Recurrence has been reported following tumor spillage at surgery.[Level of evidence: 3iiiA]
Primary Renal Synovial Sarcoma
Primary renal synovial sarcoma is a subset of embryonal sarcoma of the kidney and is characterized by the t(x;18)(p11;q11) SYT-SSX translocation. It is similar in histology to the monophasic spindle cell synovial sarcoma. Primary renal synovial sarcoma contains cystic structures derived from dilated, trapped renal tubules. Primary renal synovial sarcoma occurs more often in young adults and this type of renal tumor should be treated with different chemotherapy regimens than traditional Wilms tumor.
Anaplastic Sarcoma of the Kidney
Anaplastic sarcoma of the kidney is a rare renal tumor that has been identified mainly in patients younger than 15 years. Patients present with a renal mass with the most common sites of metastases being the lung, liver, and bones. These tumors show pathologic features similar to pleuropulmonary blastoma of childhood (see the PDQ summary on Unusual Cancers of Childhood for more information) and undifferentiated embryonal sarcoma of the liver (see the PDQ summary on Childhood Liver Cancer for more information). Optimal therapy for this diagnosis is not clear. In the past, these tumors have been identified as anaplastic Wilms tumor and treated accordingly.
For patients with suspected Wilms tumors, preoperative staging studies should include a computed tomography (CT) scan of the abdomen/pelvis and chest. Preoperative assessment of intravascular extension of Wilms tumor is essential to guide management. The presence of intravenous tumor thrombus, which has been reported in up to 11.3% of Wilms tumor cases, can lead to differences in management. In North America, local staging of Wilms tumor is performed with CT or magnetic resonance imaging of the abdomen and pelvis. Contrast-enhanced CT has high sensitivity and specificity for detection of cavoatrial tumor thrombus in Wilms tumor cases that may impact surgical approach. Routine Doppler evaluation after CT has been performed is not required.
The stage is determined by the results of the imaging studies and both the surgical and pathologic findings at nephrectomy and is the same for tumors with favorable or anaplastic histology. Thus, patients should be characterized by a statement of both criteria (for example, stage II, favorable histology or stage II, anaplastic histology).[2,3]
The staging system was originally developed by the National Wilms Tumor Study Group and still used by the Children's Oncology group. The staging system and incidence by stage are outlined below.
In stage I Wilms tumor (43% of patients), all of the following criteria must be met:
For a tumor to qualify for certain therapeutic protocols as stage I, regional lymph nodes must be examined microscopically.
In stage II Wilms tumor (20% of patients), the tumor is completely resected, and there is no evidence of tumor at or beyond the margins of resection. The tumor extends beyond the kidney as evidenced by any one of the following criteria:
Rupture or spillage confined to the flank, including biopsy of the tumor, is no longer included in stage II and is now included in stage III.
In stage III Wilms tumor (21% of patients), there is residual nonhematogenous tumor present following surgery that is confined to the abdomen. Any one of the following may occur:
In stage IV Wilms tumor (11% of patients), hematogenous metastases (lung, liver, bone, brain), or lymph node metastases outside the abdominopelvic region are present. The presence of tumor within the adrenal gland is not interpreted as metastasis and staging depends on all other staging parameters present. The primary tumor should be assigned a local stage following the above criteria which determines local therapy. For example, a patient may have stage IV, local stage III disease.
Stage V and those predisposed to developing Wilms tumor
In stage V Wilms tumor (5% of patients), bilateral involvement by tumor is present at diagnosis. Previously an attempt was made to stage each side according to the above criteria on the basis of the extent of disease. The current COG-AREN0534 protocol recommends preoperative chemotherapy in hopes of reducing tumor size to allow renal-sparing surgical procedures. In these patients, renal failure rates approach 15% at 15 years posttreatment, making renal-sparing treatment important.
Because of the relative rarity of this tumor, all patients with Wilms tumor should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) with experience treating Wilms tumor is required to determine and implement optimum treatment.
The majority of the randomized clinical studies for treatment of children with Wilms tumor have been conducted by two large clinical groups. The National Wilms Tumor Study (NWTS) Group, which is now part of the Children's Oncology Group (COG), has established standard treatment for Wilms tumor in North America, which consists of initial surgery followed by chemotherapy and, in some patients, radiation therapy.[1,2,3] The Société Internationale d'Oncologie Pédiatrique (SIOP) is a European consortium. There are differences between the two groups that affect staging and classification. The SIOP trials provide preoperative chemotherapy before definitive resection. This statement will focus on the NWTS (now COG Renal Tumor Committee) results and studies. The major treatment conclusions of the National Wilms Tumor Studies (NWTS 1–5) are as follows:
Operative principles have evolved from NWTS trials. The most important role for the surgeon is to ensure complete tumor removal without rupture and perform an assessment of the extent of disease. Radical nephrectomy and lymph node sampling via a transabdominal or thoracoabdominal incision is the procedure of choice. A flank incision should not be performed because of the limited exposure it provides. For patients with resectable tumors, preoperative or intraoperative biopsy should not be performed. Routine exploration of the contralateral kidney is not necessary if technically adequate imaging studies do not suggest a bilateral process. If the initial imaging studies are suggestive of bilateral kidney involvement and depending on the size of the tumor, biopsy or wedge resection may be performed. Alternatively, the contralateral kidney should be explored to rule out bilateral involvement. This should be done prior to nephrectomy since the diagnosis of bilateral disease would dramatically alter the approach.
Partial nephrectomy remains controversial and is not recommended except for children with bilateral tumors, children with a solitary kidney, or rare cases of horseshoe kidney. However, partial nephrectomy has been suggested for Wilms tumor in infants with Denys-Drash or Frasier syndrome in order to delay the need for dialysis.; [Level of evidence: 3iiB] Also, some children who are predisposed to bilateral tumors who have very small tumors detected by ultrasound screening may be considered for partial nephrectomy to preserve renal tissue. In North America, renal-sparing partial nephrectomy of unilateral Wilms tumor following administration of chemotherapy to shrink the tumor mass is considered investigational.[14,15]
Hilar, periaortic, iliac, and celiac lymph node sampling is mandatory even if the nodes appear normal.[10,16] Furthermore, any suspicious node basin should be sampled. Margins of resection, residual tumor, and any suspicious node basins should be marked with titanium clips. Resection of contiguous organs is rarely indicated and there is an increased incidence of complications occurring in more extensive resections involving removal of additional organs beyond the diaphragm and adrenal gland. This has led to the recommendation in current COG protocols that these patients should be considered for initial biopsy, neoadjuvant chemotherapy, and then secondary resection. Pathologically, Wilms tumor rarely invades adjacent organs. Primary resection of liver metastasis is not recommended. Wilms tumor arising in a horseshoe kidney is rare and accurate preoperative diagnosis is important in planning the operative approach. Primary resection is possible in most cases. Inoperable cases can usually be resected after chemotherapy.
Preoperative chemotherapy prior to nephrectomy is indicated in the following situations:[10,17,20,21,22,23]
Patients with massive, nonresectable unilateral tumors, bilateral tumors, or venacaval tumor thrombus extending above the hepatic veins are candidates for preoperative chemotherapy because of the risk of initial surgical resection.[10,17,20,21] Preoperative chemotherapy should follow a biopsy, except in the setting of bilateral disease (COG-AREN0534). The biopsy may be performed percutaneously through a flank approach.[24,25,26,27,28,29] Preoperative chemotherapy should include doxorubicin in addition to vincristine and dactinomycin unless there is anaplastic histology present, which then includes treatment with other agents. The chemotherapy generally makes tumor removal easier because of the decreased size and vascular supply of the tumor and may reduce the frequency of surgical complications.[17,20,29,30,31] Postoperative radiation therapy to the tumor bed is required when a biopsy is performed or in the setting of local tumor stage III.
Newborns and all infants younger than 12 months require a reduction in chemotherapy doses to 50% of those given to older children. This reduction diminishes toxic effects reported in children in this age group enrolled in NWTS studies while maintaining an excellent overall outcome. Liver function tests in children with Wilms tumor should be monitored closely during the early course of therapy based on hepatic toxic effects (sinusoidal obstructive syndrome, previously called veno-occlusive disease) reported in those patients.[34,35] Dactinomycin should not be administered during radiation therapy. Patients who develop renal failure while on therapy can continue receiving chemotherapy with vincristine, dactinomycin, and doxorubicin. Vincristine and doxorubicin can be given at full doses; however, dactinomycin is associated with severe neutropenia. Reductions in dosing these agents may not be necessary, but accurate pharmacologic and pharmacokinetic studies are needed while the patient is receiving the therapy.[36,37]
Children treated for Wilms tumor are at increased risk for developing second malignant neoplasms. Congestive heart failure has been shown to be a risk in children treated with doxorubicin with the degree of risk influenced by cumulative doxorubicin dose, radiation to the heart, and gender (females are at increased risk). Efforts, therefore, have been aimed toward reducing the intensity of therapy when possible. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)
As mentioned previously, clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, neuroepithelial tumor of the kidney, and cystic partially-differentiated nephroblastoma are childhood renal tumors unrelated to Wilms tumor. Because of their renal location, they have been treated on clinical trials developed by the NWTS Group. The approach to their treatment, however, is distinctive from that of Wilms tumor, and requires timely and accurate diagnosis by a pathologist and pediatric oncologist with experience with these types of renal tumors.
Standard Treatment Options
Table 2 describes the standard chemotherapy regimens used to treat Wilms tumor.
Table 3 provides an overview of the standard treatment based on published results for all stages of Wilms tumor and survival information.
Additional Treatment Considerations
It may be possible to treat a subset of stage I Wilms tumor patients with surgery alone without chemotherapy. The Children's Oncology Group (COG) addressed this question in the National Wilms Tumor Study-5 (NWTS-5 [COG-Q9401]) trial for children younger than 2 years at diagnosis with stage I favorable histology (FH) Wilms tumors that weigh less than 550 g. In the NWTS-5 study, the omission of adjuvant chemotherapy was tested for this group of patients. Stringent stopping rules were designed to ensure closure of the study if the 2-year relapse-free survival rate was 90% or lower. The expectation was that approximately 50% of the surgery-only children would be salvaged after recurrence thus attaining the 95% predicted survival of children with very low-risk Wilms tumor treated with standard chemotherapy according to regimen EE-4A. This study was discontinued in 1998 when the predicted 2-year EFS fell below 90%. Long-term follow-up of this study of the surgery-only cohort and the EE-4A group with a median follow-up of 8.2 years reported the estimated 5-year EFS for surgery only was 84% (95% confidence interval [CI], 73%–91%); for the EE-4A patients it was 97% (95% CI, 92%–99%, P = .002). One death was observed in each treatment group. The estimated 5-year overall survival (OS) was 98% (95% CI, 87%–99%) for surgery only and 99% (95% CI, 94%–99%) for EE-4A (P = .70). COG study COG-AREN0532 is assessing this cohort again and is evaluating biological markers for this very low-risk group.[4,6]
The outcome of patients with peritoneal implants treated with gross resection, three-drug chemotherapy, and total abdominal radiation (10.5 Gy) is similar to other stage III patients.[Level of evidence: 2A]
Stage IV disease is defined by the presence of hematogenous metastases to the lung, liver, bone, brain, or other sites, with the lung being the most common site. Previously, chest x-rays were used to detect pulmonary metastases. The introduction of computed tomography (CT) created controversy because many patients had lung nodules detected by chest CT scans that were not seen on chest x-rays. Management of newly diagnosed patients with FH Wilms tumor who have lung nodules detected only by CT scans (with negative chest x-ray) has elicited controversy as to whether they need to be treated with additional intensive treatment that is accompanied by acute and late toxicities. In a retrospective review of 186 patients from NWTS-4 and NWTS-5 (COG-Q9401) with CT-only detected lung nodules, patients who received doxorubicin in addition to vincristine and dactinomycin with or without lung radiation had a 5-year EFS of 80% versus 56% for patients receiving only two drugs (P = .004). There was no difference in the 5-year OS (87% vs. 86%).
For patients with stage IV FH Wilms tumor, the role of pulmonary irradiation has been examined retrospectively (based on chest x-ray results) and is being examined prospectively (based on CT scan results) to identify clinical and radiologic features in patients that suggest that radiation can be omitted in certain subsets.
Investigators in the United Kingdom reviewed outcomes in children with stage IV Wilms tumor with pulmonary metastases at diagnosis and the factors that contributed to the decision to withhold pulmonary radiation. Patients who underwent pulmonary irradiation had a 9-year EFS of 79% versus 53% in patients who did not, although there was no difference in OS. Pulmonary radiation decreased the chance of lung relapse (8% vs 23%). No consistent features could be identified to aid in the selection of patients who could safely avoid pulmonary radiation.
In a retrospective review of newly diagnosed patients with Wilms tumor and pulmonary metastases enrolled on the SIOP-93-01 and SIOP-WT-2001 studies, the 5-year OS was 83% and the 5-year EFS was 72% for all children (N = 207). Survival was poorer for high-risk primary tumor histology patients (5-year OS 44%, EFS 39%) than for low- and intermediate-risk patients (5-year OS 90%, EFS 77%). Complete response of patients with pulmonary metastases to 6 weeks of chemotherapy was associated with better outcome (5-year OS 91%, 5-year EFS 79%) compared with patients with stable or progressive disease (5-year OS and EFS 17%). The presence of viable tumor in the resected pulmonary metastases was associated with a poorer survival (5-year OS 55%, 5-year EFS 35%) compared with completely necrotic metastases (5-year OS 97%, 5-year EFS 85%). Of patients whose pulmonary lesions showed a complete remission to chemotherapy alone, approximately 20% relapsed.
The presence of liver metastases at diagnosis is not an independent adverse prognostic factor in patients with stage IV Wilms tumor.
Stage V and those predisposed to developing bilateral Wilms tumor
Management of a child with bilateral Wilms tumor is very challenging. The goals of therapy are to eradicate all tumor and to preserve as much normal renal tissue as possible, with the hope of decreasing the risk of chronic renal failure among these children. Traditionally, patients have undergone bilateral renal biopsies with staging of each kidney. In NWTS-4, bilateral Wilms tumor patients had a lower EFS and OS compared with patients with localized Wilms tumor (including anaplastic histology), except for stage IV patients, in which OS was higher for patients with bilateral Wilms. The NWTS-4 study reported that the 8-year EFS for patients with bilateral Wilms tumor with favorable histology was 74% and the OS was 89%; for anaplastic histology, the EFS was 40% and OS was 45%. The NWTS-5 (COG-Q9401) study reported the 4-year EFS for bilateral Wilms tumor patients was 61% and the OS was 81%; with anaplastic histology, the EFS was 44% and the OS was 55%.[2,3] Similar outcomes for patients with bilateral Wilms tumor have been reported in a single-institution experience in the Netherlands, with a 10-year OS of 78% (N = 41). In this study, there was significant morbidity in terms of renal failure (32%) and secondary tumors (20%). The incidence of end-stage renal failure in the Dutch study may be a reflection of a longer follow-up period.
Treatment has changed from an initial surgical approach to an attempt to shrink the tumor and spare renal parenchyma with preoperative chemotherapy. The first COG trial to formally study bilateral Wilms tumors (COG-AREN0534) reflects the present recommendation to not perform an initial biopsy or laparotomy. Primary tumor excision should not be attempted, but patients should be given preoperative chemotherapy consisting of vincristine, dactinomycin, and doxorubicin. In a series of 49 patients with Wilms tumor who received preoperative therapy according to the SIOP-93-01 guidelines, the timing of surgery was determined when there was no longer imaging evidence of tumor regression. The mean treatment duration was 80 days prior to nephron-sparing surgery. The 5-year EFS rate was 83.4% and the OS rate was 89.5%. All but one of the patients had nephron-sparing surgery in at least one kidney. Despite the good survival, 14% of the patients developed end-stage renal disease. In another series, nine out of ten patients with bilateral favorable-histology Wilms tumors underwent successful bilateral nephron-sparing procedures after receiving preoperative chemotherapy as detailed in a retrospective review from St. Jude Children's Research Hospital. One patient in the series developed renal failure after bilateral nephron-sparing surgery. Two patients with anaplastic histology died, although one patient died from complications of treatment rather than tumor. The OS for this group of patients was 83%. The authors recommend that bilateral nephron-sparing surgery should be considered for all patients who have bilateral Wilms tumor with favorable histology, even if preoperative imaging studies suggest that the lesions are unresectable.
For patients who are treated with preoperative chemotherapy, it is essential to evaluate the tumor pathology after 4 to 8 weeks. The ideal time to do a biopsy or resection is not clear for patients who are not being treated on a protocol, since minimal shrinkage may reflect chemotherapy-induced differentiation or anaplastic histology. However, continuing therapy without evaluating tumor pathology in a patient with bilateral Wilms tumor may increase toxicity for the patient without providing additional benefit for tumor control. Anaplastic histology occurs in 10% of patients with bilateral Wilms tumor and responds poorly to chemotherapy. Once the diagnosis is made, a complete resection should be performed. Making the diagnosis is not straightforward, since in a series of 27 patients from NWTS-4, discordant pathology was seen in 20 cases, which highlights the need to obtain tissue from both kidneys. Seven children who were eventually found to have diffuse anaplastic tumors had core biopsies performed to establish the diagnosis but anaplasia was not found on the core biopsies. Anaplasia was identified in only three out of the nine patients when an open wedge biopsy was performed and in seven out of nine patients who had a partial or complete nephrectomy.
Chemotherapy and/or radiation therapy following biopsy or second-look operation is dependent on the response to initial therapy, with more aggressive therapy required for patients with inadequate response to initial therapy observed at the second procedure or in the setting of anaplasia.[3,17,18,19,20,21,22]
Renal transplantation for children with Wilms tumor is usually delayed until 1 to 2 years have passed without evidence of malignancy. Similarly, renal transplantation for children with Denys-Drash syndrome and Wilms tumor, all of whom require bilateral nephrectomy, is generally delayed 1 to 2 years after completion of treatment for the tumor.
Inoperable Wilms tumors
In North America, standard therapy for Wilms tumor is primary nephrectomy and lymph node sampling followed by adjuvant chemotherapy. However, certain clinical presentations of Wilms tumor are referred to as inoperable Wilms tumor and include the following:
Neoadjuvant chemotherapy consisting of vincristine, dactinomycin, and doxorubicin followed by resection and radiation therapy is the usual treatment for inoperable Wilms tumor. In the case of bilateral Wilms tumor or occurrence in a solitary kidney, the purpose of chemotherapy prior to surgery is to reduce the size of the tumor and allow preservation of maximal renal parenchyma at resection. In the case of extensive vena caval infiltration, initial chemotherapy also results in tumor shrinkage and minimizes the complications associated with subsequent resection and avoids the use of cardiopulmonary bypass.
Adults with Wilms tumor
In an analysis of Wilms tumor patients in the Surveillance, Epidemiology and End Results database, adults (n = 152) had a statistically worse OS (69% vs. 88%, P < .001) than pediatric patients (n = 2,190). Adults diagnosed with Wilms tumor were more likely than pediatric patients to be staged as having localized disease, to not receive any lymph node sampling, and to not receive any radiation treatment. The investigators recommended that all adult patients diagnosed with Wilms tumor should undergo lymph node sampling and that there should be close collaboration with pediatric surgeons and oncologists in treatment planning.
Treatment Options Under Clinical Evaluation
The following treatment options are currently under investigation in Children's Oncology Group (COG) clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Anaplastic (Focal or Diffuse) Histology
The following treatment options are currently under investigation in COG clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Patients with loss of heterozygosity at chromosomes 1p and 16q will be treated with regimen M with radiation therapy to all sites of disease. Patients with metastases outside or in addition to lung metastases will be treated with regimen M and radiation therapy.
Diffuse Anaplastic (No Measurable Disease)
Diffuse Anaplastic (Measurable Disease)
The following treatment option is currently under investigation in COG clinical trials. Information about ongoing clinical trials is available from the NCI Web site. Patients with multicentric tumors, patients with high-risk bilateral tumors, and patients with diffuse hyperplastic nephrogenic rests are treated on the following protocol:
COG-AREN0534 (Combination Chemotherapy and Surgery in Treating Young Patients With Wilms Tumor): Children with bilateral tumors are eligible for COG-AREN0534, which is the first protocol to prospectively study bilateral tumors. The goals of therapy are to eradicate all tumor and to preserve as much normal renal tissue as possible with the hope of decreasing the risk of chronic renal failure among these children.[25,26] When children are identified with bilateral tumors by CT or magnetic resonance imaging, central radiologic review will be performed to exclude tumor extension, invasion, rupture, metastases, or thrombus. Central review will also assess characteristics of nephrogenic rests versus tumor and differentiate active from sclerotic rests or tumors. Biopsy will not be mandated. Upfront intensification with three drugs (vincristine, doxorubicin and dactinomycin), will be used in large part to move patients earlier to definitive surgery. Repeat imaging will be mandated at 6 weeks. Based on response to treatment surgery, biopsy or continued chemotherapy will be performed. If biopsy or surgery is performed, chemotherapy or radiation therapy will be given based on histology. Repeat imaging will be performed at 12 weeks. If there is a complete response, definitive surgery or continued therapy will be performed. This approach will identify patients with anaplasia, rhabdomyomatous differentiation, complete necrosis, or stromal differentiation, select them for early surgery, and define the intensity of chemotherapy to be administered.[16,18,27] Chemotherapy and/or radiation therapy following the second-look operation is dependent on the response to initial therapy, with more aggressive therapy required for patients with inadequate response to initial therapy observed at the second procedure.[17,18,19,20,21,22]
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I Wilms tumor, stage II Wilms tumor, stage III Wilms tumor, stage IV Wilms tumor, stage V Wilms tumor and recurrent Wilms tumor and other childhood kidney tumors. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Because of the relative rarity of this tumor, all patients with clear cell sarcoma of the kidney should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) with experience treating renal tumors is required to determine and implement optimum treatment.
The approach for treating clear cell sarcoma of the kidney is different from Wilms tumor since the OS of children with clear cell sarcoma of the kidney remains lower than for patients with favorable histology Wilms tumor. In the National Wilms Tumor Study-3 (NWTS-3), the addition of doxorubicin to the combination of vincristine, dactinomycin, and radiation therapy resulted in an improvement in disease-free survival for patients with clear cell sarcoma of the kidney. The National Wilms Tumor Study-4 (NWTS-4) showed that patients treated with vincristine, doxorubicin, and dactinomycin for 15 months had an improved relapse-free survival compared with patients treated for 6 months (88% vs. 61% at 8 years). In the National Wilms Tumor Study-5 (COG-Q9401) trial, children with stages I to IV clear cell sarcoma of the kidney were treated with a new chemotherapeutic regimen combining vincristine, doxorubicin, cyclophosphamide, and etoposide in an attempt to further improve the survival of these high-risk groups. All patients received radiation therapy to the tumor bed. With this treatment, the 5-year EFS was approximately 79% and OS was approximately 89%. Stage I patients had 100% 5-year EFS and OS. Stage II patients had a 5-year EFS of approximately 87% and OS of approximately 97%. Stage III patients had an approximately 74% 5-year EFS and an approximately 87% 5-year OS. Stage IV patients had a 5-year EFS of approximately 36% and 5-year OS of 45%. Clear cell sarcoma of the kidney has been characterized by late relapses; however, in NWTS-5, most relapses occurred within 3 years. In NWTS-5, the most common site of recurrence was the brain, which has been successfully treated with combination chemotherapy, surgery, and radiation therapy.[Level of evidence: 2A]
The following treatment option is currently under investigation in a Children's Oncology Group (COG) clinical trial. Information about ongoing clinical trials is available from the NCI Web site.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with clear cell sarcoma of the kidney. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Because of the relative rarity of this tumor, all patients with rhabdoid tumor of the kidney should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) with experience treating renal tumors is required to determine and implement optimum treatment.
Patients with rhabdoid tumors of the kidney continue to have a poor prognosis with 4-year overall survival (OS) rates of 42% for stages I and II (n = 40) and 16% for stages III, IV, and V (n = 102).
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with rhabdoid tumor of the kidney. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Optimal treatment has not been established for these tumors. Treatment according to Ewings/primitive neuroectodermal tumor protocols should be considered.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with peripheral primitive neuroectodermal tumor of the kidney. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
When diagnosed in the first 7 months of life, the 5-year event-free survival rate is 94% and the overall survival rate is 96%. In a report from the United Kingdom of 50 children with mesoblastic nephroma studied on clinical trials and 80 cases from the national registry in the same time period, there were no deaths.
A prospective clinical trial that enrolled 50 patients confirmed that complete surgical resection, which includes the entire capsule, is adequate therapy for most patients with mesoblastic nephroma. In this study, only 2 of 50 patients died. Patients were at increased risk for local and eventually metastatic recurrence if there was stage III (incomplete resection and/or histologically positive resection margin), cellular subtype, and aged 3 months or older at diagnosis. Because of the small numbers of patients and the overlapping incidence of these characteristics (5 of 50 patients), the significance of the individual characteristics could not be discriminated. Adjuvant chemotherapy has been recommended for patients who share these three characteristics, though the benefit of adjuvant therapy will remain unproven with such a low incidence of disease. Although incompletely resected, stage III infants younger than 2 months may not need chemotherapy.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with congenital mesoblastic nephroma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Survival of patients with renal cell carcinoma (RCC) is affected by stage of disease at presentation and the completeness of resection at radical nephrectomy. Overall survival rates range from 64% to 87%. The 5-year survival for stage I is 90% or higher, for stages II and III it is 50% to 80%, and for stage IV it is 9%, which is similar to the stage-for-stage survival in RCC in adults. Retrospective analyses and the small number of patients involved place limitations on the level of evidence in the area of treatment. The primary treatment for RCC includes total surgical removal of the kidney and associated lymph nodes. In two small series, patients who had partial nephrectomies seemed to have outcomes equivalent to those who had radical nephrectomies. Partial nephrectomy may be considered in carefully selected patients with low-volume localized disease.[2,3] There is some suggestion that regional lymph node involvement does not portend the same poor prognosis as adult renal cell carcinoma. However, this is controversial as the finding are based on only 13 patients. Treatment of unresectable metastatic disease is presently unsatisfactory, similar to adult RCC; it is poorly responsive to radiation and there is no effective chemotherapy regimen. Immunotherapy, such as interferon-alpha and interleukin-2, may have some effect on cancer control. Rare spontaneous regression of pulmonary metastasis may occur with resection of the primary tumor. Several targeted agents (for example, sorafenib, sunitinib, bevacizumab, temsirolimus, pazopanib, and everolimus) have been approved for use in adults with RCC; however, these agents have not been tested in pediatric patients with RCC. However, a case report of an adolescent with a TFE-3 RCC suggests responsiveness to multiple tyrosine kinase inhibitors. (Refer to the PDQ summary on adult Renal Cell Cancer Treatment for more information.)
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood renal cell carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Approximately 15% of patients with favorable histology Wilms tumor and 50% of patients with anaplastic Wilms tumor experience recurrence. Historically, the salvage rate for patients with recurrent favorable histology Wilms tumor was 25% to 40%. As a result of modern treatment combinations, the outcome after recurrence has increased up to 60%.[2,3] A number of potential prognostic features influencing outcome post-recurrence have been analyzed, but it is difficult to separate whether these factors are independent of each other. In addition, the following prognostic factors appear to be changing over time as therapy for primary and recurrent Wilms tumor evolves:
NWTS-5 showed that time to recurrence and site of recurrence were no longer prognostically significant.[2,5] However, patients who experienced a pulmonary relapse within 12 months of diagnosis had a poorer prognosis (5-year OS, 47%) than did patients who experienced a pulmonary relapse 12 months or more after diagnosis (5-year OS, 75%).
Based on the above, the following three risk categories have been identified:
Treatment of Standard-Risk Relapsed Wilms Tumor
In children who had small, stage I Wilms tumor and were treated with surgery alone, the EFS was 84%. All but one child who relapsed was salvaged with treatment tailored to the site of recurrence. Wilms tumor patients whose initial therapy consisted of immediate nephrectomy followed by chemotherapy with vincristine and dactinomycin who relapse can be successfully retreated. Fifty-eight patients were treated on the National Wilms Tumor Study-5 (COG-Q9401) relapse protocol with surgical excision when feasible, radiation therapy, and alternating courses of vincristine, doxorubicin and cyclophosphamide, and etoposide and cyclophosphamide. Four-year EFS after relapse was 71% and overall survival (OS) was 82%. For patients whose site of relapse was only the lungs, the 4-year EFS rate was 68% and OS rate was 81%.
Treatment of High-Risk Relapsed Wilms Tumor
Approximately 50% of unilateral Wilms tumor patients who relapse or progress after initial treatment with vincristine, dactinomycin, and doxorubicin and radiation can be successfully retreated. Sixty patients were treated on the NWTS-5 relapse protocol with alternating courses of cyclophosphamide/etoposide and carboplatin/etoposide, surgery, and radiation therapy. The 4-year EFS rate with high-risk Wilms tumor was 42% and OS rate was 48%. For high-risk patients who relapsed in the lungs only the 4-year EFS rate was 49% and OS rate was 53%.
Patients with stages II, III, and IV anaplastic-histology tumors at diagnosis have a very poor prognosis upon recurrence. The combination of ifosfamide, etoposide, and carboplatin has demonstrated activity in this group of patients, but significant hematologic toxic effects have been observed. While high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation has been utilized for recurrent high-risk favorable-histology patients,[10,11,12] an intergroup study of the former Pediatric Oncology Group and the former Children's Cancer Group used a salvage induction regimen of cyclophosphamide and etoposide (CE) alternating with carboplatin and etoposide (PE) followed by delayed surgery. Disease-free patients were assigned to maintenance chemotherapy with five cycles of alternating CE and PE, and the remainder of patients to ablative therapy and autologous marrow transplant. All patients received local radiation therapy. The 3-year survival was 52% for all eligible patients, while the 3-year survival was 64% for the chemotherapy consolidation subgroup and 42% for the autologous marrow transplant subgroup.; [Level of evidence: 2A] The outcome of hematopoietic stem cell rescue in selected patients may be superior;[12,14] however, patients with gross residual disease going into transplant do not do as well. Patients in whom such salvage attempts fail should be offered treatment on available phase I or phase II studies.
Treatment of Recurrent Clear Cell Sarcoma of the Kidney
Treatment of patients with recurrent clear cell sarcoma of the kidney depends on initial therapy. Cyclophosphamide and carboplatin should be considered if not used initially. Patients with recurrent clear cell sarcoma of the kidney involving the brain have responded to treatment with ifosfamide, carboplatin, and etoposide (ICE) coupled with local control consisting of either surgical resection and/or radiation.[Level of evidence: 2A] In NWTS-5, patients with clear cell sarcoma of the kidney and brain metastases have been successfully treated with combination chemotherapy, surgery, and radiation therapy.
Patients with recurrent rhabdoid tumor of the kidney, clear cell sarcoma of the kidney, neuroepithelial tumor of the kidney, and renal cell carcinoma should be considered for treatment on available phase I and phase II clinical trials.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent Wilms tumor and other childhood kidney tumors. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added text about the results of an analysis of Wilms tumor patients in the Surveillance, Epidemiology and End Results database that found that adults had a statistically worse overall survival than pediatric patients. Also added text to state that the investigators recommended that all adult patients diagnosed with Wilms tumor should undergo lymph node sampling and that there should be close collaboration with pediatric surgeons and oncologists in treatment planning (cited Kalapurakal et al. as reference 9, Reinhard et al. as reference 10, and Ali et al. as reference 11).
Added text to state that while little is known about the biology of clear cell sarcoma of the kidney, the t(10;17)(q22;p13) translocation has been reported in clear cell sarcoma of the kidney. As a result of the translocation, the YWHAE-FAM22 fusion transcript is formed; this was detected in 12% of clear cell sarcoma of the kidney cases in one series (cited O'Meara et al. as reference 16).
Treatment of Wilms Tumor
Added text about the results from a series of 49 patients with Wilms tumor who received preoperative therapy according to the SIOP-93-01 guidelines, and how the timing of surgery was determined when there was no longer imaging evidence of tumor regression (cited Sudour et al. as reference 15).
Added Adults with Wilms tumor as a new subsection.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of Wilms tumor and other childhood kidney tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Wilms Tumor and Other Childhood Kidney Tumors Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/wilms/HealthProfessional. Accessed <MM/DD/YYYY>.
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Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.
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For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.
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There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.
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Last Revised: 2012-11-27
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Last modified on: 2 April 2014